Toxicological Sciences最新文献

{"title":"Acute exposure to diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) impacts pituitary hormones and inflammatory markers, suggesting altered reproductive aging in adult female mice.","authors":"Yinka Ojo, Karen Weis, Mary Laws, Catheryne Chiang, Ramses Santacruz-Marquez, Francky Maemble Ntomb, Jodi Flaws, Lori Raetzman","doi":"10.1093/toxsci/kfag020","DOIUrl":"10.1093/toxsci/kfag020","url":null,"abstract":"<p><p>Phthalates are ubiquitous endocrine-disrupting chemicals whose exposure is associated with accelerated reproductive aging in humans. We focused on the pituitary gland, the source of the gonadotropins: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH). We hypothesized that the common phthalates di-(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) modulate inflammation in the pituitary and impact gonadotropin expression acutely and during aging. To test this, female CD-1 mice were orally dosed with corn oil or varying concentrations of DEHP and DiNP for 10 days. Pituitary tissues were collected immediately after dosing or 15 months post-dosing, processed, and analyzed by quantitative real-time PCR (qPCR) and immunohistochemistry. We found that acute phthalate exposure did not alter Fshb and Lhb mRNA expression compared with controls, but both DEHP and DiNP reduced FSH immunopositive cell number. Phthalate exposure also decreased Il1b, and increased Il18 and Tnf mRNA levels compared with controls, suggesting an inflammatory imbalance. At 15 months post-dosing, DiNP exposure increased Lhb and Il1b mRNA levels, but repressed Fshb and Nlrp3 mRNA levels compared with controls. Next, using dissociated cultures, we investigated the impact of phthalates and the proinflammatory stimulus lipopolysaccharide (LPS) on inflammation and gonadotropin gene expression directly at the pituitary. Both the DEHP metabolite MEHP and LPS decreased Fshb, but not Lhb mRNA relative to control. MEHP also repressed the induction of Il1b by LPS. Together, these findings suggest that acute exposure to phthalate alters mRNA expression of inflammatory markers and gonadotropins in the pituitary, which could alter the process of reproductive aging.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.","authors":"Sean V Murphy, Shiny A P Rajan, Kevin Lindert, Tracey Young, Yan Jiao, Yu Zhou, Oula Khoury, Malcolm McSwain, Sivanandane Sittadjody, Zeeshan Hamid, Phillip W Clapp, Timothy S Leach, Timothy C Orr, Douglas Shankle, Emily Whitaker, Khiry Sutton, Steven E Albertson, Kristina Stumpf, Lysette Mutkus, Trang Simon, Gauri Kulkarni, Jeannie Chan, Jingyun Lee, Laura A Cox, Ge Li, Charity Campbell, Michael Olivier, Sobha Puppala, Tony E Reeves, Carl D Langefeld, Hannah C Ainsworth, Julie Ziegler, Amy Zinnia, Mohammad S Khan, Frank C Marini, Stephen J Walker, Thomas D Shupe, Alan Jacobson, Cristina M Furdui, Andrew C Bishop, Adam R Hall, Michael C Seeds, Kimberly D Reeves, Anthony Atala","doi":"10.1093/toxsci/kfaf179","DOIUrl":"10.1093/toxsci/kfaf179","url":null,"abstract":"<p><p>There is a critical need to understand pathophysiological mechanisms involved in injury from acute chlorine gas (Cl2) exposure. Limited information is available regarding the time course and mechanisms of injury after acute Cl2 exposure due to a lack of human clinical data and limited fidelity of pre-clinical animal models. We designed and integrated a Cl2 exposure platform to generate and deliver precise concentrations of Cl2 to a microfluidic human airway-on-a-chip microphysiological system. Chemical, biological, structural, and functional airway-on-a-chip responses to Cl2 exposure were characterized across multiple concentrations, exposure times, and post-exposure timepoints. Transcriptomics and metabolomics analyses delineated key molecular, cellular, and physiological pathways involved in the acute response to Cl2 exposure. This work represents a significant advancement towards high-throughput, human-relevant characterization of pulmonary toxicants and medical countermeasure development, addressing critical gaps in toxicology modeling while reducing reliance on animal studies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145821038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ToxPoint: the case study for respiratory sensitization assessment of methyl methacrylate using new approach methodologies.","authors":"Frank Faulhammer, Susanne N Kolle, Karin Wiench","doi":"10.1093/toxsci/kfag008","DOIUrl":"10.1093/toxsci/kfag008","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian hormone deficiency enhances wood smoke-induced immune dysfunction via transcriptomic and metabolic alterations.","authors":"Mijung Oh, Sydnee Yazzie, Eunju Lim, Onamma Edeh, Charlotte McVeigh, Alicia Bolt, Jennifer M Gillette, Katherine E Zychowski","doi":"10.1093/toxsci/kfag023","DOIUrl":"10.1093/toxsci/kfag023","url":null,"abstract":"<p><p>The increasing frequency and severity of wildfires have heightened public exposure to smoke, highlighting the importance of identifying susceptibility factors, including ovarian hormone deficiency. Here, we used single-cell RNA sequencing to profile bone marrow immune cells from ovariectomized (OVX) mice exposed to either filtered air (FA) or wood smoke (WS), followed by functional validation in macrophages from both OVX and Sham-operated mice. Single-cell analyses focused on the OVX context; interactions between surgery and exposure were confirmed at the functional level in assays that included both Sham and OVX groups. In OVX mice, WS broadly suppressed transcriptional programs involved in antigen processing, leukocyte activation, antiviral defense, and bone remodeling. This was associated with altered immune cell composition, including increased memory CD8+ T cells and decreased granulocytes and interferon-responsive populations. Bone marrow-derived macrophages (BMDMs) from WS-exposed OVX mice displayed metabolic reprogramming, characterized by the reversal of OVX-induced suppression of oxidative phosphorylation and glycolytic activity, along with reduced expression of M2-associated genes, without concurrent induction of M1-associated genes. This immune-metabolic decoupling suggests that WS exposure under ovarian hormone deficiency may imprint a lasting program in the bone marrow macrophage axis. Together, these findings show that ovarian hormone deficiency increases vulnerability to WS-induced immune disruption in the bone marrow. WS triggers macrophage reprogramming only under ovarian hormone deficiency, leading to heightened metabolic activity alongside suppression of key immune pathways, identifying a novel mechanism of immunotoxicity. These findings emphasize the need to consider hormonal status in air pollution risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13014470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the mechanisms of Cupferron reproductive toxicity: insights from in vitro assays, network toxicology, and molecular docking.","authors":"Mustafa Daşman, Mohammed T Qaoud, Mahmoud Abudayyak","doi":"10.1093/toxsci/kfag014","DOIUrl":"10.1093/toxsci/kfag014","url":null,"abstract":"<p><p>Cupferron, widely used in industrial and analytical contexts, has been proposed as a potential nitric oxide (NO) donor; however, its effects on the male reproductive system remain unclear. We assessed toxicity in TM3 (Leydig) and TM4 (Sertoli) mouse cells. Cytotoxicity (6 to 0.0035 mg/ml) was measured by MTT/NRU; genotoxicity by comet assay; oxidative stress markers (MDA, 8-OHdG, GSH, SOD) and testosterone by ELISA; cell death and ROS by flow cytometry; and gene expression by RT-qPCR. MTT IC50 values were 0.131 mg/ml (TM3) and 0.219 mg/ml (TM4). At 0.125 mg/ml, comet assay revealed markedly increased DNA damage, ≥ 16-fold (P ≤ 0.05) in both TM3 and TM4 cells. In TM4, MDA and 8-OHdG rose ≥ 1.3-fold, while SOD activity increased in both TM3 (1.2-fold) and TM4 (1.5-fold) cells (P ≤ 0.05). Annexin V/PI analysis indicated increased necrosis without significant changes in apoptosis. Testosterone levels were unaffected at all doses. RT-qPCR showed upregulation of SOD1, HMOX1, GSTA1, GPX1 antioxidant genes in both TM3 and TM4 (P ≤ 0.05). Network toxicology highlighted NOS1, NOS3, and PTGS2 as putative targets, supported by docking indicating high affinity and substrate-like poses, implicating modulation of oxidative/inflammatory pathways. ADMETLab 3.0 predicted genotoxic, hepatotoxic, and carcinogenic risks. Overall, Cupferron induces oxidative stress, DNA damage, necrosis, and antioxidant gene activation in Leydig and Sertoli cells, supporting potential male reproductive toxicity and the need for comprehensive in vivo and mechanistic in vitro studies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants.","authors":"Timothy A Crombie, Ryan Mckeown, Samuel J Widmayer, Amanda O Shaver, Nicolas D Moya, J B Collins, Janneke Wit, Robyn E Tanny, Christian Braendle, Lewis Stevens, Lisa Van Sluijs, Matthew V Rockman, Mark G Sterken, Marie-Anne Félix, Erik C Andersen","doi":"10.1093/toxsci/kfag019","DOIUrl":"10.1093/toxsci/kfag019","url":null,"abstract":"<p><p>Genetic differences among individuals shape how they respond to environmental toxicants, but the identification and validation of the genes responsible for this variation is difficult, particularly in humans. Consequently, our limited knowledge of the genes that influence susceptibility constrains our ability to accurately predict the risks posed by environmental toxicants. To identify genes underlying natural differences in toxicant susceptibilities, we measured the effects of 23 environmental toxicants on larval development across 195 genetically diverse Caenorhabditis elegans strains using a high-throughput imaging platform. We then combined these response data with whole-genome sequences to perform genome-wide association mappings, identifying 40 genomic regions where genetic variants are correlated with susceptibility differences. Many of these regions are enriched for genes involved in biological processes previously linked with toxicant responses, supporting the potential contributions of these genes to natural variation in susceptibility. Using biologically informed heuristics based on genomic context and functional annotation, we prioritized genes for follow-up experimentation and identified 94 candidate susceptibility genes, offering feasible targets for experimental validation that could ultimately inform toxicant risk prediction and regulatory assessment by linking genetic variation to differences in susceptibility. Analysis of natural genetic variation among 195 wild C. elegans strains identified 94 candidate genes putatively linked to differences in susceptibility to 23 environmental toxicants. These findings can inform the discovery of conserved susceptibility genes and the development of biomarkers that improve chemical risk assessment by accounting for genetic differences among humans.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146221048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review of nervous system effects of ethylbenzene exposure in animal models.","authors":"Laura V Dishaw, Michele M Taylor, Deborah Segal, Laura M Carlson","doi":"10.1093/toxsci/kfag016","DOIUrl":"10.1093/toxsci/kfag016","url":null,"abstract":"<p><p>Ethylbenzene is a high-production-volume chemical. Exposure occurs in the general population, but there is potential for additional exposure in certain groups, such as workers in petrochemical industries or individuals living near contaminated areas. This paper presents a systematic review of currently available evidence in animals focused on potential nervous system-related effects of ethylbenzene exposure. A broad literature search was conducted. A total of 9,679 studies were screened for inclusion based on Populations, Exposures, Comparators, and Outcomes (PECO) criteria. Included studies were evaluated for potential concerns related to risk of bias and sensitivity, and informative studies moved forward for data extraction and evidence synthesis. Twenty-one animal toxicology studies were identified that evaluated nervous system effects, including auditory effects, neurotransmitters, neurobehavior, brain weight, and histopathology. Six studies rated medium or low confidence showed consistent concentration- and exposure duration-related effects on cochlear hair cells and hearing thresholds. The evidence for the other nervous system outcomes is inconclusive. Although some studies showed effects on neurotransmitters and neurobehavior, they were rated low confidence, and findings were inconsistent. Relative brain weight changes were observed, but the direction of the effect was inconsistent. No changes were observed in absolute brain weights, which is considered the more reliable measure for evaluating effects on brain weight. No changes in brain histopathology were reported.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using fish models to understand the role of aryl hydrocarbon receptor (AHR)-interacting protein (AIP) in controlling sensitivity and resistance to dioxin-like compounds in vivo.","authors":"Sibel I Karchner, Neelakanteswar Aluru, Diana G Franks, Chesna A Mandl, Jared V Goldstone, Tara Burke, Denise Champlin, Jane K La Du, Dante M Perone, Spencer Stinson, Lisa Truong, Bryan W Clark, Diane Nacci, Robyn L Tanguay, Mark E Hahn","doi":"10.1093/toxsci/kfag033","DOIUrl":"10.1093/toxsci/kfag033","url":null,"abstract":"<p><p>Humans are exposed to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) that cause toxicity through activation of the aryl hydrocarbon receptor (AHR). There is inter-individual variation in sensitivity to the effects of AHR ligands, but it is not fully explained by variation in the AHR. A clue to the genetic mechanisms underlying differential sensitivity to AHR agonists has emerged from studies of Atlantic killifish (Fundulus heteroclitus) populations with evolved tolerance to PCBs, TCDD, and PAHs. Genomic studies of these populations identified AHR-interacting protein (AIP/Ara9/XAP2) as the strongest candidate resistance gene. However, the precise role of AIP in the mechanism of resistance is unknown. To understand the role of AIP in the toxicity of dioxin-like compounds in vivo, we used CRISPR-Cas9 to generate AIP loss-of-function alleles in killifish and zebrafish (Danio rerio). Homozygous mutant killifish and zebrafish die during larval development-by 30 and 12 d postfertilization, respectively-whereas heterozygous mutants develop, survive, and reproduce normally. During embryonic and early larval stages, homozygous mutant zebrafish exhibit reduced sensitivity to embryotoxic effects of exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126) and TCDD. Gene expression profiling of aip-deficient larvae revealed hundreds of differentially expressed genes. PCB126 induced similar sets of well-known AHR-regulated genes in mutant and wild-type larvae, although with reduced magnitude overall in AIP mutants. This study highlights the important role of AIP in fish larval development and demonstrates that AIP status can influence the response of vertebrate embryos to dioxin-like compounds in vivo.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147469346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zonal hepatocellular responses to acute ethanol consumption: impacts on mitochondrial function and liver metabolism.","authors":"Matthew T Savoca, Kenji Takemoto, Jiangting Hu, Li Li, Zhi Zhong, John J Lemasters","doi":"10.1093/toxsci/kfag013","DOIUrl":"10.1093/toxsci/kfag013","url":null,"abstract":"<p><p>Hepatocellular mitochondrial depolarization (mtDepo) after ethanol (EtOH) increases respiration to stimulate EtOH detoxification. mtDepo also triggers mitophagy, which may contribute to alcohol-associated liver disease. This study characterized sublobular respiration and distribution of mtDepo and mitophagy after acute EtOH. C57BL/6J and GFP-LC3 transgenic mice were gavaged with 6 g/kg EtOH or vehicle and administered MitoTracker Red (MTR). Hepatocytes were zonally sorted by MTR fluorescence for assessment of oxygen consumption rates (OCRs). Cytochrome P4502E1 (CYP2E1) immunolabeling identified central halves of liver lobules. After vehicle, MTR localized to mitochondria throughout lobules, indicating polarization, with higher OCRs in periportal (PP) hepatocytes compared with pericentral (PC). After EtOH, MTR fluorescence became diffuse in CYP2E1-positive central halves of lobules, signifying mtDepo, whereas portal halves remained polarized. GFP-LC3 puncta marking mitophagy also increased predominantly in central halves. Surface hepatocytes accessible by multiphoton microscopy were CYP2E1-positive and developed mtDepo and GFP-LC3 puncta after EtOH. After hepatocyte isolation, mtDepo reversed shown by rhodamine 123 uptake. At 6 h post-EtOH, OCRs approximately doubled in both PP and PC hepatocytes, returning to baseline by 24 h, but PC displayed greater proportional increases. Acute EtOH induces mtDepo and mitophagy predominantly in central halves of lobules, including within <50 μm of the liver surface. Although mtDepo reverses after isolation, elevated respiratory capacity persists. Due to central half mtDepo, PP and PC hepatocytes contribute about equally to the respiratory burst after EtOH.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction of: Vitrigel-Eye Irritancy Test Method Using HCE-T Cells.","authors":"","doi":"10.1093/toxsci/kfag032","DOIUrl":"https://doi.org/10.1093/toxsci/kfag032","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}